Light collection system

ABSTRACT

The present teachings provide a detection cell for a biological material and methods for detecting biological material including a photosensitive material optically coupled to an interior volume containing the biological material so to avoid optical components or an external light source.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims a priority benefit under 35 USC §119(e) fromU.S. Patent Application No. 60/626,784 filed Nov. 9, 2004, which isincorporated herein by reference.

FIELD

The present teaching relate to methods and systems for detection ofbiological samples.

INTRODUCTION

Detection of results from assays on biological samples is usually doneby detection of emission light from the biological samples. Typically,excitation light is provided by an external light source to excite amoiety of the biological sample to provide emission light. The directionof excitation light to the biological sample from the external lightsource and the direction of emission light to a detector from thebiological sample require optical components to direct the light, suchas lenses, mirrors, gratings, prisms, etc. External light source andassociated optical components add complexity and size to detectionsystems. It is desirable to select assays for the biological samplesthat do not use external light sources and associated opticalcomponents.

Assays that do not use external light sources and associated opticalcomponents provide results in the form of luminescent light. Luminescentlight originates from inside the biological sample. Since excitationlight does not have to reach the biological sample detection can occurin the vicinity of the biological sample. It is desirable to providedetection of the luminescent light in the vicinity of the sample.Collection of the luminescent light can be provided by the container ofthe biological material. It is desirable to provide a container thatcollects the luminescent light for detection in the vicinity of thesample.

SUMMARY

In various embodiments, the present teachings provide a detection cellfor a biological material including an interior volume adapted tocontain the biological material, and a photosensitive material opticallycoupled to the interior volume, the photosensitive material beingadapted to detect light emitted from the biological material in theinterior volume.

In various embodiments, the present teachings provide a method fordetection of a biological material including transporting the biologicalmaterial to an interior volume, emitting light from a luminescentreaction of the biological material, and detecting the light emittedfrom the biological material in an interior volume of the detectioncell, wherein the light is emitted without an external light source.

Some advantages of the present teaching will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or may be learned by practice of the various embodiments.The advantages of the embodiments will be realized and attained by meansof the elements and combinations particularly pointed out in theappended claims.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not to be restrictive of the embodiments, as claimed.

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several embodiments and togetherwith the description, serve to explain the principles of the presentteaching.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a representative biological detectioncell according to various embodiments of the present teachings;

FIG. 2 is a perspective view of a representative biological detectioncell according to various embodiments of the present teachings;

FIG. 3 is a perspective view of a representative biological detectioncell according to various embodiments of the present teachings;

FIG. 4 is a perspective view of a representative biological detectioncell according to various embodiments of the present teachings;

FIG. 5A is a cross-sectional view of a representative biologicaldetection cell according to various embodiments of the presentteachings;

FIG. 5B is a cross-sectional view of a representative biologicaldetection cell according to various embodiments of the presentteachings; and

FIG. 6 illustrates a representative biological detection systemaccording to various embodiments of the present teachings;

FIG. 7 illustrates an example of an assay that can generate luminescentlight;

FIG. 8 illustrates a graph showing the intensity of luminescent lightdetected from different directions relative an internal volume; and

FIG. 9 illustrates a graph showing the relative intensity of luminescentlight detection from different directions relative to an internalvolume.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory only,and are intended to provide an explanation of various embodiments of thepresent teachings.

DESCRIPTION OF THE EMBODIMENTS

In this application, the use of the singular includes the plural unlessspecifically stated otherwise. In this application, the use of “or”means “and/or” unless stated otherwise. Furthermore, the use of the term“including”, as well as other forms, such as “includes” and “included”,is not limiting. Also, terms such as “element” or “component” encompassboth elements and components comprising one unit and elements andcomponents that comprise more than one subunit unless specificallystated otherwise. Wherever possible, the same reference numbers will beused throughout the drawings to refer to the same or like parts.

The section headings used herein are for organizational purposes only,and are not to be construed as limiting the subject matter described.All documents cited in this application, including, but not limited topatents, patent applications, articles, books, and treatises, areexpressly incorporated by reference in their entirety for any purpose.In the event that one or more of the incorporated literature and similarmaterials differs from or contradicts this application, including butnot limited to defined terms, term usage, described techniques, or thelike, this application controls.

The term “optically coupled” as used herein refers to the ability topropagate light without the used of optical components to direct thelight, such as lenses, mirrors, gratings, prisms, etc. According to thepresent teachings, the interior volume containing the biologicalmaterial or the container walls are not optical components, but can beused to channel the emission light from the biological material to thephotosensitive material.

The term “external light source” as used herein refers to a source ofirradiance that can provide excitation that results in fluorescentemission. External light sources can include, but are not limited to,white light, halogen lamp, laser, solid state laser, laser diode, diodesolid state lasers (DSSL), vertical-cavity surface-emitting lasers(VCSEL), LEDs, phosphor coated LEDs, organic LEDs (OLED), thin-filmelectroluminescent devices (TFELD), phosphorescent OLEDs (PHOLED),inorganic-organic LEDs, LEDs using quantum dot technology, LED arrays,an ensemble of LEDs, a floodlight system using LEDs, and/or white LEDs,filament lamps, arc lamps, gas lamps, and fluorescent tubes. Externallight sources can have high irradiance, such as lasers, or lowirradiance, such as LEDs. The different types of LEDs mentioned abovecan have a medium to high irradiance.

The term “photosensitive material” as used herein refers to anycomponent, portion thereof, or system of components that can interactwith, alter the path of, and/or detect light including a reflectivematerial, mirror, charged coupled device (CCD), back-side thin-cooledCCD, front-side illuminated CCD, a CCD array, a photodiode, a photodiodearray, a photo-multiplier tube (PMT), a PMT array, complimentarymetal-oxide semiconductor (CMOS) sensors, CMOS arrays, an avalanchediode structure, a charge-injection device (CID), CID arrays, etc. Thedetector can be adapted to relay information to a data collection devicefor storage, correlation, and/or manipulation of data, for example, acomputer, or other signal processing system.

Photosensitive material can provide multi-color detection bymulti-layered material with each layer sensitive to a different color.For example, the color photodetectors organized in three layers within asensor to form full-color pixels (Foveon, Inc., Santa Clara, Calif.). Bydedicating three color photodetectors for each pixel, images aresharper, have better color detail, and are more immune to colorartifacts. Alternatively, photosensitive material in multi-colorphotodiodes can provide multi-color detection. Examples of suchphotodiodes include those based on silicon and gallium arsenic.

The term “interior volume” as used herein refers to any structure, suchas a sample region, channel, micro-fluidic channel, or chamber thatprovides containment for a sample, such as a biological material in aliquid or solid sample. The interior volume can be bounded by walls thatcan be opaque or transparent and can include a semiconductor material,such as silicon, germanium, silicon germanium, gallium arsenide, etc.;or an insulator, such as glass, SiO₂, fused silica, etc.; polymers, oran organic-inorganic hybrid material.

In various embodiments, an organic-inorganic hybrid material forcontaining a solid sample can be one obtained by a sol-gel method. Insuch embodiments, the interior volume can be bound by a sol-gel or theinterior volume itself can be a sol-gel. Examples of sol-gels includethose using precursors such as 3-trimethoxysilylpropyl methacrylate(MPTS, H₂C═C(CH₃)CO₂(CH₂)₃Si(OCH₃)₃, made by Aldrich Chemical) andheptadecafluorodecyl trimethoxysilane (PFAS, CF₃(CF₂)₇(CH₂)₂Si(OCH₃)₃,made by Toshiba). The two precursors, MPTS and PFAS, can be mixed withwater in presence of 0.05N hydrochloric acid (HCl) as a catalyst forsol-gel reaction. After stirring the solution of MPTS(3), PFAS(1) andwater(2) in the presence of 0.05N HCl (where the bracketed numbersindicate molar equivalents) for 9 hours at 60° C., a totally transparentsolution can be obtained. Subsequently, the transparent solution can befiltered through a 0.22 λm-size filter to remove impurities and gasbubbles. The filtered solution can be kept still for 30 minutes toremove gas bubbles resulting from the stirring and filtering. Thefiltered solution can be used as the internal volume where biologicalsamples filter in via diffusion. Alternatively, the filtered solutioncan be used to coat the boundary of the internal volume. For example,the sol-gel can be coated onto a p-doped Si(100) wafer by spin-coatingat 2000 rpm for 30 seconds. Finally, the coated film can then be curedthermally for 12 hours at 150° C. UV (200-260 nm) by light irradiation,using for example, a Oriel 82511 Hg/Xg lamp, which gives a power densityof 45 mJ/cm².

Further, the interior volume can take any shape including a well, atube, a channel, a micro-fluidic channel, a vial, a cuvette, acapillary, a cube, an etched channel plate, a molded channel plate, anembossed channel plate, etc. The interior volume can be part of acombination of multiple interior volumes grouped into a row, an array,an assembly, etc. Multi-chamber arrays can include 12, 24, 36, 48, 96,192, 384, or more, interior volume chambers.

The term “biological material” as used herein refers to any biologicalor chemical substance, alone or in solution, with components that canemit light in a liquid sample or solid sample. Examples of luminescentmoieties that can be included in biological material are listed in Table1 with emission wavelengths and fluorescent concentrations (Albrecht,Steffen, et al. Chemiluminescence: Reaction systems and theirapplication under special consideration of biochemistry and medicine,Huthig GhbH, Heidelberg, Germany, pp. 9-10, 1996):

TABLE 1 Emission Wavelength φ_(CL) Luminescent Moiety (max. in nm)(Einstein/mol) Luminol 424 0.01 Isoluminiol 425 0.001 Lucigenin 530 0.02Aryloxalate + Fluorescer — 0.05-0.50 p-Chlorophenyl 475 10⁻⁶-10⁻⁸Magnesium Bromide Bacterial Luciferine/ 460-480 0.05-0.30 LuciferasenAequorin 469 0.15-0.20 Pholasin 495 0.10 Firefly Luciferine/ 565 0.90Luciferase Adamantandioxetane 477 10⁻⁴ (in DMSO bis 0.20)The biological material can include luminescent labels that can combinewith luminescent moieties in a detection reaction or can be luminescentthemselves to provide detection of certain analytes in the biologicalmaterial; examples of which are listed in Table 2 showing examples ofluminescence including chemiluminescence (CL) and bioluminescence (BL)(Albrecht, Steffen, et al. Chemiluminescence: Reaction systems and theirapplication under special consideration of biochemistry and medicine,Huthig GmbH, Heidelberg, Germany, pp. 35-36, 1996):

TABLE 2 Luminescent Label Detection Reaction Analyte Acridiniumester+H₂O₂/OH → CL T₃, T₄, TSH, FT₃, FT₄, CKMB, Ferritin, βHCG, PSA, Vit.B₁₂, auto-Thyroid AK, Folsr., LH, FSH, Prolactin, HGH, PTH, CortisolAequorin +Ca²⁺→ BL Progesteron, Transferrin Alkaline Phosphatase +AMPPD→CL AFP, CA 125, CA 19-9, CA 15-3, TSH, LH, HGH, Thyroid diagnostics,Fertility, Anemia ATP Firefly Luciferin- T₄, Myoglobin Luciferase⁺→ BLβ-Galactosidase, sensing Peroxyoxalate-CL T₄ γ-CyclodextrinGlucoseoxidase H₂O₂ by Peroxyoxalate-CL Glucose in aqueous solutionFirefly Luciferase BL Methotrexat Fluorescin Peroxyoxalate-CL IgGRhodamin Peroxyoxalate-CL LDL Glucoseoxidase H₂O₂ by Peroxyoxalate-CL17-Hydroxyprogesteron Glucose-6-phosphate NAD(P)H-dependent BLProgesteron, LH, Prolactin, hydrogenase AFP Haemin Catalysis ofLuminol-CL β2-Microglobulin Horseradish-Peroxidase Catalysis ofLuminol-CL AFP, CEA, Ferritin, LH, FSH, Progesteron, T₃, T₄, FT₃, FT₄,TSH, TBG, Cortisol, Estriol, Estradiol Horseradish-Peroxidase Catalysisof Thyroid diagnostics, Blot Acridanoxidation techniques Luminol- orIsoluminol H₂O₂/Catalyst → CL Thyroid diagnostics, derivative Fertility,Tumor marker, Reproduction, Cortisol, Progesteron Bacterielle LuciferaseBL Immuoglobuline NAD⁺ BL Estriol Pyruvatkinase ATP-dependent Firefly-BLTransferrin, Insulin Xanthinoxidase H₂O₂-generation + Luminol IgE,Prolactin, T₄, TSH → CLExamples of these luminescent labels and luminescent moieties inbiological material are manufactured by companies like Byk Sangtec, CibaCorning, Nichols Diagnostics, Brahms GmbH, Boeringer Mannheim,Millipore, Celcius Limited, and Biotrace Limited. In variousembodiments, the luminescent moiety can be dioxetane. Dioxitane canprovide a detection reaction with alkaline phosphatase luminescentlabel. Example of such reactions can detect antibodies in lysed cells(U.S. Pat. No. 6,686,171).

The biological material can include one or more nucleic acid sequencesto be monitored. The biological material can be monitored by polymerasechain reaction (PCR) and other reactions such as ligase chain reaction,antibody binding reaction (immunoassay), oligonucleotide ligationsassay, and hybridization assay. In various embodiments, the biologicalmaterial can also be subjected to thermal cycling or iso-thermalcycling. In various embodiments, the biological material can besubjected to an electric current. An example of an immunoassay isillustrated by FIG. 7 providing a biological material that can reactwith an electrode to provide electrochemiluminescence. In variousembodiments, the electrode used to generate the electrochemiluminescecan also provide current for manipulating the biological material in aliquid. For example, electrowetting on a diaelectric (U.S. Pat. No.6,565,727).

The biological material can include a combination of luminescentmoieties that generate different and spectrally distinguishableluminescence. For example, the biological sample can include differentanalytes, labels, and/or luminescent moieties that emit light atdifferent wavelengths to provide multi-color detection. In variousembodiments, luminescent moieties can be paired with fluorescent dyessuch that emission wavelengths of the luminescent moieties can activatethe fluorescent dyes. Such pairing can provide better spectralseparation and facilitate multi-color detection for end-pointquantitation and/or real-time detection. Examples of fluorescent dyeswith desirable excitation and emission wavelengths can include 5-FAM™,SYBR Green, TET™, VIC™, JOE, TAMRA, NED, ROX, CY3, Texas Red, CY5, etc.The present teaching applies at least to red dyes, green dyes, and bluedyes.

The term “refractive material” as used herein refers to any materialthat can reflect a predetermined wavelength of light. Refractivematerials can be metals that reflect all wavelengths. Refractivematerials can be a coating, a distinct layer, or a various componentsdescribed herein can themselves act as a reflective materials. Someexemplary reflective materials include, for example, insulators, such asSiO₂, TiN, SiON; semiconductor materials, such as silicon, germanium,silicon germanium, and compound semiconductors; polymers, such asTeflon®, Teflon® AF; an organic-inorganic hybrid material as disclosedabove, or any other reflective material that will be known to one ofordinary skill in the art. In various embodiments, the refractivematerial can permit external light to penetrate the internal volume tomanipulate the biological material, but not provide excitation. Forexample, biological material in liquid can be manipulated by opticallyactivated electrowetting on dielectrics (U.S. Pat. App. 2003/0224528 A1)and optically activated dielectrophoresis (Chiou, P. Y., et al., A NovelOptoelectri Tweezer Using Light Induced Dielectrophoresis, Proceeding ofIEEE/LEOS Intl Conf. Optical MEMS, pp 8-9, 2003).

The term “on” as used herein can be any of on an exterior surface, on aninterior surface, or inside of a material.

An embodiment of the present teaching shown in FIG. 1 includes adetection cell 10 including an interior volume 20, a wall 30, and aphotosensitive material 40. Photosensitive material 40 can be opticallycoupled to interior volume 20. As used herein, the term opticallycoupled is understood to mean that light emitted in the interior volume20 is capable of reaching photosensitive material 40. Moreover, interiorvolume 20 can be adapted to contain a sample, such as a liquid 50 thatcan be in contact with a biological material 60. Further, in variousembodiments, interior volume 20 can include at least one closed end 70.In various embodiments, interior volume 20 can be filed with a solid,such as a sol-gel permitting biological material 60 to diffuse into thesol-gel. The sol-gel can include conditions for the detection reaction,for example, suspension of the luminescent label.

In various embodiments, the biological material 60 can be transported tothe interior volume 20 along with the liquid 50 or the liquid 50 can bereceived by the interior volume 20 separately. When the biologicalmaterial 60 is in contact with the liquid 50, the biological material 60can emit light, shown in FIG. 1 with arrows 80. For example, the liquidcan contain a luminescent label that causes the detection reaction withan analyte. In this instance, the biological material is both theanalyte before the detection reaction, the reaction complex of analytewith luminescent label and after reacting to produce emission light.

In various embodiments, the biological material can emit either a singleor a narrow band of light, or the biological material can emit multiplewavelengths or multiple narrow bands of light. Moreover, in variousembodiments, multiple biological materials including multiple analytes,multiple luminescent labels, etc. can be received by the interior volume20. Multiple wavelengths or multiple narrow bands can be opticallycoupled to the photosensitive material 40 and can be spectrally resolvedby a detector connected to the photosensitive material 40. For example,a first biological material can produce a first wavelength. Similarly, asecond biological material can produce a second wavelength. Each of thefirst and second wavelengths can be optically coupled to thephotosensitive material 40 and they can be detected and resolved by adetector (not shown).

In various embodiments, some examples of which will be described below,the photosensitive material 40 can be positioned on interior volume 20.For example, an exterior surface 91, an interior surface 92, and/or theinside 93 of wall 30, can include photosensitive material 40. Thephotosensitive material 40 can also be positioned on an end 70 ofinterior volume 20 and/or wall 30. Similarly, “on an end” is understoodto be any of on an exterior surface (not shown), an interior surface(not shown), or inside of end 70 (not shown). Further, “on an end” isunderstood to mean substantially at the end of the interior volumeand/or wall 30. For example, the photosensitive material can bepositioned such as to provide a gap for liquid to pass from the interiorvolume to the exterior of the wall, where the gap is sufficiently narrowto permit the interior volume and/or the wall to be optically coupled tothe photosensitive material. In certain embodiments, the photosensitivematerial 40 can be positioned on all or a portion of interior volume 20and/or wall 30. Further, in various embodiments, photosensitive material40 can be manufactured to form interior volume 20, end 70, and/or wall30.

The light from the biological material is emitted within the interiorvolume 20 without the use of an external light source. In variousembodiments, because the biological material is surrounded by theinterior volume 20, the photosensitive material will detect asubstantial amount of the emitted light. As such, there are smallerlosses from embodiments described herein than in other systems.

In various embodiments there is a detection cell 200, such as amicro-fluidic biological material detector, as shown in FIG. 2,including a first surface 210 a and a second surface 210 b that whentouched together form a sandwich structure. Detection cell 200 alsoincludes an interior volume 220 that can be defined by first surface 210a and second surface 210 b. In various embodiments, first surface 210 aand second surface 210 b can be formed on a wall 230, which serves as asubstrate to support the surfaces. Further, in certain embodiments,detection cell 200 can further include an end (not shown) positioned atthe end of interior volume 220. Detection cell 200 can also include aphotosensitive material 240 optically coupled to interior volume 220and/or the end of interior volume 220.

In various embodiments at least one of first surface 210 a, secondsurface 210 b, and wall 230 can include a semiconductor material, suchas silicon, germanium, gallium arsenide, etc.; an insulator, such asSiO₂; fused silica; plastic; or any other suitable material that cansupport interior volume 220. In various embodiments, Teflon® AF can beon the interior volume 220 and/or on wall 230.

In various embodiments, the interior volume can be bound by a flexiblesheet film. This film could be thick enough to create the interiorvolume over a flat substrate. Most existing CCD system are sold with aprotective clear material to protect the photosensitive materialunderneath. Rather than forming the interior volume in thephotosensitive material, the interior volume can be shaped by theflexible sheet film to provide optical coupling with the off-the-shelfCCD.

In various embodiments, the luminescent labels can be deposited on theflexible sheet film forming the interior volume such that the biologicalmaterial emits light from the surface of the flexible sheet. In variousembodiments, the photosensitive material can be positioned to beproximate to the location on the flexible sheet film where theluminescent labels are located to provide increased collection ofemission light.

In various embodiments, the interior volume 220 can be formed in atleast one of the first surface 210 a and second surface 210 b. Theinterior volume 220 can be formed by standard etching, casting, ormolding techniques, or by other techniques as will be known to one ofordinary skill in the art.

In various embodiments, interior volume 220 can serve as a waveguide.For example, the index of refraction of the interior of interior volume220, and/or its contents, can be greater than the index of refraction ofthe first surface 210 a, second surface 210 b, and walls 230. As such,light can be channeled through the waveguide by total internalreflection as will be known to one of ordinary skill in the art.

In various embodiments, at least one of first surface 210 a, secondsurface 210 b, wall 230, and the end of interior volume 220 can includevarious photosensitive materials 240. For example, in an embodiment,first surface 210 a and second surface 210 b can include a reflectivematerial and the end of interior volume 220 can include thephotosensitive material, such as, for example, a CCD structure, aphotodiode, or a portion of a photomultiplier tube. In anotherembodiment, at least one of first surface 210 a and second surface 210 bcan include the photosensitive material 240. It will be understood thatvarious combinations of photosensitive materials 240 can be used oninterior volume 220. A substantial portion of the light emitted insideof interior volume 220 can be optically coupled to the photosensitivematerial 240.

In various embodiments, the biological material 60 can be transported tothe interior volume 220 along with the liquid 50 or the liquid 50 can bereceived by the interior volume 220 separately. As described above, whenthe biological material 60 can emit light under the proper conditions.In various embodiments, the biological material can emit either a singleor a narrow band of light, or the biological material can emit multiplewavelengths or multiple narrow bands of light. Moreover, in variousembodiments multiple biological materials can be received by theinterior volume 220. Multiple wavelengths or multiple narrow bands canbe optically coupled to the photosensitive material 240 and can bespectrally resolved by a detector connected to the photosensitivematerial 240. For example, a first biological material can produce afirst wavelength. Similarly, a second biological material can produce asecond wavelength. Each of the first and second wavelengths can beoptically coupled to the photosensitive material 240 and they can bedetected and resolved by a detector (not shown).

The biological material 60 and the liquid 50 are surrounded by theinterior volume 220. A substantial amount of the emitted light iscontained inside interior volume 220 is detected by the photosensitivematerial 240. In situations where one of first surface 210 a and secondsurface 210 b includes a reflective or refractive material, the lightemitted by the of biological material 60 is reflected or refracted backinside of interior volume 220 and is detected by photosensitive material240.

In various embodiments, after the emitted light has been monitored, theliquid sample 50 and the biological material 60 can be purged from thedetection cell 200.

In various embodiments, there is a detection cell 300, such as amicro-fluidic biological material detector, as shown in FIG. 3,including a light channeling structure 330, such as the wall of a tubesurrounding an interior volume 320. The light channeling structure 330further includes a first surface 310 a around a second surface 310 b.The detection cell 300 further includes a photosensitive material 340,such as, for example, a CCD, a photodiode, or a photomultiplier tube,positioned on at least an end 370 of the interior volume 320.

It is to be understood that the light channeling structure 330 canassume any applicable shape. For example, the light channeling structurecan be a cylindrical, rectangular, square, oval, etc. Further, the lightchanneling structure can have a uniform diameter or it can be tapered.Moreover, the light channeling structure can include any of silica,SiO₂, plastic, or any suitable waveguide material. In variousembodiments, the light channeling structure can be mounted onto asubstrate.

In various embodiments, the interior volume 320 and/or its contents, caninclude a first refractive index, and the light channeling structure 330can include a second refractive index. In general, the first and secondrefractive indexes are adjusted such that light inside the channel isinternally reflected within the interior volume 320.

In various embodiments, at least one of the first surface 310 a and thesecond surface 310 b can include a reflective material such that lightimpinging the reflective material from inside the interior volume 320 isreflected back inside the interior volume. In an embodiment, areflective material can be on the first surface 310 a. In this case,light emitted from the interior volume 320 can be transmitted throughthe second surface 310 b. Upon reaching the first surface 310 a, thelight is sent back into the interior volume 320. In another embodiment,a reflective material can be on the second surface 310 b. In this case,light emitted in the interior volume 320 that reaches the second surface310 b is sent back into the interior volume 320. In yet anotherembodiment, the material of the light channeling structure 330 betweenthe first surface 310 a and the second surface 310 b can include agraded refractive index. In this case, light having a particularwavelength can be sent back into the interior volume 320. In any case,light sent back into the interior volume 320 can be channeled throughthe interior volume 320. A substantial portion of the light emittedinside of interior volume 320 can be optically coupled to thephotosensitive material 340 and the light can be detected by a detector(not shown) coupled to the photosensitive material 340.

In various embodiments, the biological material 60 can be transported tothe interior volume 320 along with the liquid 50, or the liquid 50 canbe received by the interior volume 320 separately. As described above,when the biological material 60 can emit light. In various embodiments,the biological material can emit either a single or a narrow band oflight, or the biological material can emit multiple wavelengths ormultiple narrow bands of light. Moreover, in various embodiments,multiple biological materials can be received by the interior volume320. In either case, when multiple wavelengths or multiple narrow bandsare emitted, they can be spectrally resolved by a detector connected tothe photosensitive material 340. For example, a first biologicalmaterial can produce a first wavelength. Similarly, a second biologicalmaterial can produce a second wavelength. Each of the first and secondwavelengths can be optically coupled to the photosensitive material 340and they can be detected and resolved by a detector (not shown).

Light emitted by the biological material can be channeled through thewaveguide formed by interior volume 320 and can be detected by thephotosensitive material 340. Because the biological material 60 and theliquid 50 is surrounded by the interior volume 320, a substantial amountof the emitted light can be contained inside interior volume 320 andsent to the photosensitive material 340 for detection. In situationswhere one of first surface 310 a and second surface 310 b includes areflective material, the light emitted by the biological material 60 andliquid 50 is sent back to interior volume 320 and is detected byphotosensitive material 340.

In various embodiments after the emitted light has been monitored, theliquid 50 and the biological material 60 can be purged from thedetection cell 300.

In various embodiments there is detection cell 400, such as amicro-fluidic biological material detector, as shown in FIG. 4 includinga light channeling material 430, such as the wall of a tube surroundingan interior volume 420. The light channeling material 430 furtherincludes a first surface 410 a around a second surface 410 b. Thedetection cell 400 further includes a photosensitive material 440, suchas a CCD, a photodiode, or a photomultiplier tube positioned on andoptically coupled to at least an end 470 of the interior volume 420.

It is to be understood that the light channeling material 430 can assumeany applicable shape. For example, the light channeling material 430 canbe a cylindrical, rectangular, square, oval, etc. Further, the lightchanneling material can have a uniform diameter or it can have tapering.Moreover, the light channeling material can include any of silica, SiO₂,plastic, or any suitable waveguide material. In various embodiments, thelight channeling material 430 can be mounted onto a substrate (notshown).

In various embodiments, the interior volume 420 and/or its contents caninclude a first refractive index, and the light channeling material caninclude at least a second refractive index. In general, the first andsecond refractive indexes are adjusted such that light inside theinterior volume 420 is transmitted through the second surface 410 b andis internally reflected by the first surface 410 a such that the lightis internally reflected and stays within the light channeling material430.

For example, in various embodiments, a reflective material can be on thefirst surface 410 a. In this case, light emitted from the interiorvolume 420 can be transmitted through the second surface 410 b. Uponreaching the first surface 410 a, the light is internally reflected backinto the wall of the light channeling material 430. In anotherembodiment, a reflective material can be on the second surface 410 b. Inthis case, light emitted in the interior volume 420 that reaches thesecond surface 410 b initially transmits through the second surface 410b and is confined within the light channeling material 430 between thefirst surface 410 a and the second surface 410 b. In yet anotherembodiment, the light channeling material 430 between the first surface410 a and the second surface 410 b can include a graded refractiveindex. In this case, as will be understood by one of ordinary skill inthe art, particular wavelengths of light can be confined to differentdistances between the first surface 410 a and the second surface 410 b.In any case, light confined within the light channeling material 430 canbe channeled through the light channeling material 430 and the light canbe detected by the photosensitive material 440.

In various embodiments, the biological material 60 can be transported tothe interior volume 420 along with the liquid 50, or the liquid 50 canbe received by the interior volume 420 separately. As described above,the biological material 60 can emit light. In various embodiments, thecombination can emit either a single or a narrow band of light, or thecombination can emit multiple wavelengths or multiple narrow bands oflight. Moreover, in various embodiments, multiple biological materialscan be received by the interior volume 420. In either case, whenmultiple wavelengths or multiple narrow bands are emitted, they can bespectrally resolved by a detector connected to the photosensitivematerial 440.

Light emitted by the biological material can be channeled through thewaveguide formed by light channeling material 430 and can be detected bythe photosensitive material 440. Because the biological material 60 andthe liquid 50 is surrounded by the light channeling material 430, whichserves as a waveguide, the emitted light is contained inside lightchanneling material 430 by total internal reflection. Further, thephotosensitive material 440 will detect substantial amounts of theemitted light. In situations where one of first surface 410 a and secondsurface 410 b includes a reflective material, the light emitted by thebiological material 60 is confined within the light channeling material430 and is detected by photosensitive material 440.

For example, a first biological material can produce a first wavelength.Similarly, a second biological material can produce a second wavelength.Each of the first and second wavelengths can be optically coupled to thephotosensitive material 440 and they can be detected and resolved by adetector (not shown).

In various embodiments, after the emitted light has been monitored, theliquid sample 50 and the biological material 60 can be purged from thedetection cell 400.

In various embodiments, there is a detection cell 500, such as amicro-fluidic biological material detector, as shown in FIGS. 5A and 5B.The detection cell 500 includes a first semiconductor material 510 aincluding a first dopant of a first conductivity type positioned aroundan interior volume 52. The detection cell 500 further includes a secondsemiconductor material 510 b around the first semiconductor material 510a. The second semiconductor material includes a second dopant of asecond conductivity type.

In various embodiments, the first and second semiconductor materials caninclude silicon, germanium, silicon germanium, compound semiconductormaterials such as III-V, and II-VI semiconductors, and any othercompound semiconductor material. Further, the first and second dopantscan be boron, arsenic, phosphorous, or any semiconductor dopant materialthat will be known to one of ordinary skill in the art.

In various embodiments, the detection cell 500 further includes aninsulating material 512, such as SiO_(x), GeO, etc., contacting an innersurface 514 of the first semiconductor material. Insulating material 512can be transparent to certain wavelengths of light emitted in theinterior volume 520.

In various embodiments, the first and second semiconductor material 510a and 510 b of detection cell 500 can form an avalanche breakdownsystem. Light emitted in the interior volume 520 can be opticallycoupled to the interface of the first and second semiconductormaterials. For example, light emitted in the interior volume 520impinging the interface of the first and second semiconductor materialscan cause a stimulated emission of electrons. Further, in variousembodiments, the detection cell 500 can further include a detector (notshown) coupled to the first and second semiconductor materials adaptedto detect stimulated electrons. The detector can generate a data signalthat includes information about the stimulated electrons.

In various embodiments, the detection cell 500 can further include avoltage supply (not shown) electrically connected between the first andsecond semiconductor materials 510 a and 510 b. The voltage supply canestablish a bias, such as a forward bias or reverse bias, between thefirst and second semiconductor materials that can assist in thegeneration of the stimulated emission. In various embodiments, thevoltage supply can include a piezoelectric element.

It is to be understood that the first and second semiconductor materialscan 510 a and 510 b can assume any applicable shape. For example, thefirst and second semiconductor materials 510 a and 510 b can form acylinder, rectangle, square, oval, etc. Further, the first and secondsemiconductor materials 510 a and 510 b can have a uniform diameter orcan be tapered. In various embodiments, the first and secondsemiconductor materials 510 a and 510 b can be mounted onto a substrate(not shown).

In various embodiments, the biological material 60 can be transported tothe interior volume 520 along with the liquid 50, or the liquid 50 canbe received by the interior volume 520 separately. The biologicalmaterial 60 can emit light. In various embodiments, the biologicalmaterial can emit either a single or a narrow band of light, or thebiological material can emit multiple wavelengths or multiple narrowbands of light. Moreover, in various embodiments, multiple biologicalmaterials s can be received by the interior volume 520. In either case,when multiple wavelengths or multiple narrow bands are emitted, they canseparately stimulate electrons at the interface of the first and secondsemiconductor materials 510 a and 510 b.

For example, a first biological material can produce a first wavelength.Similarly, a second biological material can produce a second wavelength.Each of the first and second wavelengths can be optically coupled to theinterface to the two semiconductor materials. The wavelengths can thenbe detected and resolved by a detector (not shown).

Because the biological material 60 and the liquid 50 are surrounded thefirst and second semiconductor materials 510 a and 510 b, a substantialamount of the emitted light impinges the interface between the first andsecond semiconductor materials 510 a and 510 b.

In various embodiments, after the emitted light has been monitored, theliquid 50 and the biological material 60 can be purged from thedetection cell 500.

In various embodiments, there is a biological detection system 600, asshown for example in FIG. 6, including an input port 611, a firstchannel 615 connected to the input port 611, a detection cell 618connected to the first channel, and an interior volume 620. Thedetection cell 618 includes a photosensitive material (not shown). Thebiological detection system 600 further includes a display 650 thatdisplays a data signal representative of light emitted in the interiorvolume 620.

In various embodiments, the biological material detection system 600further includes a processor 660 that processes and converts the signalrepresentative of the emitted light into the data signal that can bedisplayed on display 650.

In various embodiments, the biological material can be deposited intoinput port 611 and transported to the detection cell 618 and intointerior volume 620 along with a liquid, or the liquid can be receivedby the interior volume 620 separately. As described above, thebiological material can emit light. In various embodiments, thecombination can emit either a single or a narrow band of light, or thecombination can emit multiple wavelengths or multiple narrow bands oflight. Moreover, in various embodiments, multiple biological materialscan be received by the interior volume 620. In either case, whenmultiple wavelengths or multiple narrow bands are emitted, they can bedetected by photosensitive material.

For example, a first biological material can produce a first wavelength.Similarly, a second biological material can produce a second wavelength.Each of the first and second wavelengths can be optically coupled to thephotosensitive material 440, and they can be detected and resolved bythe detection system.

The photosensitive material can generate a signal that is representativeof the emitted light. The signal can then be processed by processor 660.Processor 660 then generates a data signal that can be displayed ondisplay 650 in a visual format readable by a user.

Example

FIGS. 8 and 9 show the results of an example of a detection cell forbiological material. A 2.5 microliter luminescent reaction was set upcontaining 2×10-13 moles of pyrophosphate, ATP sulfurlase,adenosine-5′-O-phosphosulfate and luciferase. The reaction was combinedin a tube and then introduced into a glass capillary (0.4 mm insidediameter, 0.86 outside diameter, 15 mm in length). Light intensityproduced by the reaction was quantified using a Turner TD 20/20luminometer. Luminescence was measured from five different orientationsof the capillary using the same capillary and reaction. Each of themeasurements were taking over 25 seconds. FIG. 8 shows the results ofintensity over time. The five data sets for the five orientationsresulted in line 810 representing light from capillary wall and ends,line 830 representing light from one end of the capillary, line 840representing light from the capillary wall only (ends taped with blacktape), line 820 representing light from one end of the capillary(capillary wall covered by reflective tube holder), line 800representing light from the capillary wall (ends taped with black tapeand covered by reflective tube holder). The data from the chart of FIG.8 is adjusted to determine the light emission detected by the PMT asrelative intensity versus capillary orientation. FIG. 9 shows theaverage real-time data stream over the 25 seconds. The relativeintensity block 900 representing the light from the capillary wall wassignificantly less than the relative intensity block 910 representingthe light from one capillary end. Hence, the capillary was able to actas a light guide and concentrate the emission light to ends of thecapillary.

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a photosensitive material” includes two or morephotosensitive materials. Furthermore, the use of the term “including”,as well as other forms, such as “includes” and “included”, is notlimiting.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of thepresent teachings. Thus, it is intended that the various embodimentsdescribed herein cover other modifications and variations within thescope of the appended claims and their equivalents.

1. A detection cell for a biological material, the detection cellcomprising: an interior volume adapted to contain the biologicalmaterial; and a photosensitive material optically coupled to theinterior volume, the photosensitive material being adapted to detectlight emitted from the biological material in the interior volume. 2.The detection cell for biological material of claim 1, wherein thephotosensitive material forms the interior volume.
 3. The detection cellfor biological material of claim 2, further comprising a sandwichstructure comprising at least two charge coupled devices, wherein the atleast two charge coupled devices comprise the interior volume.
 4. Thedetection cell for biological material of claim 2, the interior volumeis adapted to contain a liquid or solid.
 5. The detection cell forbiological material of claim 2, wherein the photosensitive materialforms an exterior layer of the interior volume.
 6. The detection cellfor biological material of claim 2, wherein the photosensitive materialforms an interior layer of the interior volume.
 7. The detection cellfor biological material of claim 1, wherein the photosensitive materialis part of at least one of a charge coupled device, a photodiode, and aphotomultiplier tube.
 8. The detection cell 0 for biological material ofclaim 7, wherein the photosensitive material is part of a channel formedaround the interior volume.
 9. The detection cell for biologicalmaterial of claim 18, further comprising an avalanche breakdown system.10. The detection cell for biological material of claim 2, wherein thebiological material comprises at least one of chemiluminescent labelednucleic acids and chemiluminescent labeled cells.
 11. A method fordetection of a biological material, the method comprising: transportingthe biological material to an interior volume; providing a photosensitive material optically coupled to the interior volume; emittinglight from a luminescent reaction of the biological material; anddetecting the light emitted from the biological material in an interiorvolume of the detection cell, wherein the light is emitted without anexternal light source.
 12. The method for detection of biologicalmaterials of claim 11, further comprising channeling the emitted lightwithin a waveguide.
 13. The method for detection of biological materialsof claim 12, wherein channeling the emitted light further comprisesreflecting the emitted light into the interior volume.
 14. The methodfor detection of biological materials of claim 12, wherein channelingthe emitted light comprises refracting the emitted light in a wall ofthe detection cell. 15-20. (canceled)